Composition for the treatment of hypertrophied oral tissue

ABSTRACT

1. A TOOTHPASTE COMPOSITION CONTAINING THEREIN AN ALKALLOID SELECTED FROM THE GROUP CONSISTING OF AROMATIC AMINES HAVING BETWEEN ABOUT 6 TO 10 CARBON ATOMS AND ALIPHATIC AMINES HAVING BETWEEN ABOUT 4 TO 7 CARBON ATOMS, SAID ALKALOID BEING PRESENT IN AN AMOUNT OF FROM 0.0125 TO 5.0 PERCENT BY WEIGHT OF THE TOOTHPASTE COMPOSITION.

nitecl States Patent O 3,839,552 COMPOSITION FOR THE TREATMENT OF HYPERTROPHIED ORAL TISSUE Carl M. Kosti, 704 Foxhall Road, Bloomfield Hills, Mich. 48013 No Drawing. Continuation-impart of application Ser. No.

829,793, July 2, 1969, which is a continuation-in-part of application Ser. No. 742,535, July 5, 1968, now abandoned. This application Mar. 19, 1971, Ser. No. 126,376 The portion of the term of the patent subsequent to Apr. 13, 1988, has been disclaimed Int. Cl. A61k 7/16 US. Cl. 424-54 8 Claims ABSTRACT OF THE DISCLOSURE A toothpaste composition for the simultaneous cleansing of the teeth and treatment of hypertrophied or hyperplastic gums. The toothpaste contains as an essential component thereof one or more alkaloids, such as the sympathomimetic amines, which are vasoconstrictors and effect vasoconstriction of the gums.

RELATED APPLICATIONS This application is a continuation-in-part of my copending application Ser. No. 829,793, filed July 2, 1969, now Pat. No. 3,574,859, issued Apr. 13, 1971, which is entitled Process for the Treatment of Hypertrophied Gums which application is a continuation-inpart of my application Ser. No. 742,535, filed July 5, 1968, now abandoned.

BACKGROUND OF THE INVENTION This invention relates to a composition for the treatment of hypertrophied or hyperplastic, and overgrown gums and to application of alkaloids such as sympathomimetic amines which are vasoconstrictors, to the oral tissues for effecting such treatment.

Another object of this invention is to provide a composition for prevention of oral tissue hypertrophy.

More particularly the object of this invention is to provide a toothpaste formulation incorporating such an alkaloid for effecting such treatment.

Enlargement of the gums is a condition featuring increase in the size of the gingiva. If the increase in the size is due to the increase in the number of cells, then the enlargement is referred to as hyperplastic; if the increase in size of the gums is due to the increase in size of the cells themselves then the enlargement is said to be hypertrophic. [t is difiicult to clinically differentiate between hypertrophy and hyperplasia and only microscopically can the differentiation be made. Therefore, the terms hypertrophy and hyperplasia are used interchangeably.

Almost all practicing dentists and most physicians, especially those in the field of neurology, ear-nose and throat, allergy, and internal medicine, have at one time or another in the normal course of their practice encountered patients exhibiting hypertrophy or hyperplasia of the oral tissues. 'Gingival hypertrophy or hyperplasia is a result of local or systemic causes. Some of the local causes are: ill fitting prosthesis, faulty restorations, irritation to orthodontic appliances, irirtation to calculus formation in the sulcus of the gums, tissue irritation during extraction, only to mention a few. Some of the systemic causes are: systemic intake of diphenylhydantoin sodium and like agents in the treatment of epilepsy and the like convulsions, diabetes, vitamin imbalance, chemical poisoning, local tissue irritation due to systemic inflammatory activity, and others. One of the significant side effects of systemic intake of diphenylhydantoin sodium in treatment of epilepsy and like convulsions is hyperplasia of the oral tissues. The treatment of choice held most eifective by the majority of clinicians knowledgeable in the field of periodontology is gingivectomy (cutting away of the hyperplastic tissue around the necks of teeth) if the condition is not too severe or complete clearance of dentition (full mouth extraction) if hyperplasia has progressed to a point when it interferes with mastication. This treatment is very painful and traumatic for the patient and the incidence of recurrence of hypertrophy or hyperplasia is common, about of the cases, so that gingivectomy must be performed at frequent intervals. This invention relates to a composition for the treatment of hyperplastic or hypertrophied gums which has not been suggested before and is novel in its pharmacodynamic action on the enlarged tissue, without the necessity of surgical intervention. The mode of the pharmacologic action of this invention is twofold: one, it removes the chemical irritants from the tissues through the venous circulation of the capillary bed, and two, by its vasoconstriction on the arterial end of the capillary bed deprives the overgrown tissues from the nutritional elements preventing the growth of the cells and resulting in decrease in the size of the cells.

Microscopically, hypertrophic or hyperplastic tissue exhibits proliferation of many well differentiated young fibroblasts among which some inflammatory cells may be present. Inflammation may be associated with gingival hyperplasia or hypertrophy with inflammation being secondary to fibrosis. Removal of the source of irritation, when possible, will cause inflammation to disappear but the fibrous tissue hyperplasia remains. Heretofore there is no known therapeutic treatment for cure or control of hyperplasia or hypertrophy. Surgical removal of excess tissue is about the only reliable treatment for this condition; however, recurrence of hyperplasia or hypertrophy of the oral tissues is certain to reappear after a few months.

The present invention overcomes the aforesaid problems and disadvantages. It provides a sure and safe effective treatment for hypertrophied and hyperplastic oral tissues which have not become fibrous, substantially eliminating the need for surgery. In the case of epileptics it can be utilized without interrupting the use of diphenylhydantoin sodium or other anticonvulsant agents.

Application of the composition of this invention to the oral tissues will readily penetrate the outer keratinous epithelial layer, since this layer has affinity for hydrophilic substances, break the electrical polarization that exists between the acidic epithelium and alkaline submucosa at the basement membrane and diffuse into the deeper submucous tissues. Brushing or massaging of the gums will facilitate absorption of the active agent. Once the active ingredient, the sympathomimetic amine, gains entrance into the ground substance of the submucosa it acts directly on the chemoresptors of the endothelial cells of the capillary membrane causing swelling of the cells thereby decreasing the lumen of the capillaries and restoring the patency of the arteriols. This vasoconstriction of the arteriols and capillaries (the venuoles are not affected appreciably) stops the escape of the chemical or physical irritants into the tissues restoring the normal balance of vascular and extravascular fluid exchange. This restoration of the normal fluid exchange and capillary wall permeability prevents the irritants from entering the tissues which are essential in stimulation of the fibroblasts to secrete collagen in formation of fibrous network. Any chemical or physical irritant stimulates the fibroblasts to secrete collagenous material which is precipitated outside the cells forming interconnected bundles of the insoluble collagenic threads. This process of fiber formation is called fibrosis. The sympathomimetic amine prevents the formation of the fibrous bundles and thusly decreases the volume of the tissues. Re-establishment of the capillary patency deprives the tissues of their nutritional requirements thusly starving the hypertrophied or hyperplastic cells to death. Once the escape of irritants into the tissues is stopped by the vasoconstriction of the arterial end of the capillary bed, the venous end of the capillary bed which is not affected by the sympathomimetic amine reabsorbs the irritants already in the tissues back into the circulation. This entire process illustrates the pharmacotherapeutic action of my invention on hypertrophied or hyperplastic oral tissues.

SUMMARY OF THE INVENTION This invention pertains to a toothpaste composition which is uniquely suited for the treatment of hypertrophied or hyperplastic gums due to the inclusion in the composition of a vascoconstricting alkaloid in an amount of from about 0.0125 to 5.0 weight percent of the composition. Preferred alkaloids for use in this invention are aromatic amines having between about 6 to carbon atoms and aliphatic amines having between about 4 to 7 carbon atoms.

DESCRIPTION OF THE PREFERRED EMBODIMENT I have found that the conditions of hyperplasia or hypertrophy can be effectively treated by incorporating into a toothpaste from about 0.2125 to 5.0 Weight percent, based on the total weight of the toothpaste composition, of an alkaloid which is a vasoconstricting sympathomimetic amine. The following table indicates the general dosage needed to treat various hypertrophic or hyperplastic conditions.

4 5. Hydroxyamphetamine HO.C H .CH CHCH .NH 6. Paredrinol HO.C H .CH CHCH .NHCH 7. Methoxyphenamine CH O.C H .CH CHCH .NHCH

III. Disubstituted:

l. Epinine (HO) .C H .CH .CH .NHCH

2. Levarterenol (HO)2.C H .CHOH.CH .NH

3. Epinephrine (HO) 2.C H .CHOH.CH .NHCH

4. Methoxamine 5. Oxymetazoline 6-tert-butyl-3(2-imidazoline-2 yl methyl) 2,4-dimethylphenol B. Aliphatic Nucleus 1. Tuaminoheptane CH (CH CHCH .NH

2. Methylhexaneamine CH CH .CHCH .CH .CHCH .NH

S CH2. CHCHz.NHCHa 4. Propylhexedrine S CH1. CHCH;.NHCH;

3. Cyclopentamine TABLE I Amount of tissue enlargement Severe Mild to moderate Daily hygle ne g in Mg./ce. 533 2 Mg./ec. iiel Mg./cc. fillffl lf yi fi dliiillfiffiiiiiitj:::::::: 0.52.33? 0.55. 2 soi'zlfili 0.1555722 1 Not generally recommended.

In obtaining the new and novel treatment, this inven- EXAMPLE 1 tion makes use of certain alkaloid compounds or substances which are sympathomimetic amines, and which possess among other properties those of serving as decongestants or vasoconstrictors effecting shrinkage of the overgrown oral tissues. Preferred are aromatic amines having between six to ten carbon atoms, and aliphatic amines having a total of between four to seven carbon atoms. Some examples of useful compounds are:

A. Aromatic Nucleus I. Unsubstituted:

. Phenylethylamine C H .CH .CH .NH

. Phenylethanolamine C H .CHOH.CH .NH .Amphetamine C H .CH .CHCH .NH

. Dextro-amphetamine Isomer of amphetamine .Methamphetamine C H .CH .CHCH .NHCH

. Mephentermine C H .CH .CHCH H.CH

. Phenylpropanolamine C H .CHOH.CHCH .NH Ephedrine C H .CHOH.CHCH .NHCH

. N aphazollue C uH C H: fi-NH-CEH: N CH;

10. Phenylpropylmethylamine C H CHCH .CH .NHCH

II. Monosubstituted:

1. T yramine HO.C H .CH .CH-NH 2. S-hydroxytriptamine 3. Synephrine HO.C H .CHOH-CH .NHCH 4. Phenylephrine C H OH.CHOH.CH .NHCH

Each 90 cc. (3 fluid oz. tube) of the toothpaste will contain:

Mg. 0 Phenylephrine hydrochloride (pure) 900.0 Glycerin U.S.P. (Glycerol) 1,000.0 Propylene glycol U.S.P 18,0000 Methylparaben 100.0 saccharine sodium solution 100.0 Peppermint oil 300.0 Mineral oil 1,000.0 Sodium lauryl sulfate 2,500.0 Dicalcium phosphate (in very fine powder form) 54,000.0 Sodium carboxymethylcellulose U.S.P. 120 H 900.0 Distilled water 11,2000 Sodium bisulfite 180.0

The above formula will result in one percent phenylephrine hydrochloride toothpaste from which different concentrations of phenylephrine hydrochloride can readily be obtained by increasing or decreasing the amount of the sympathomimetic amine. The ingredients were thoroughly mixed together into a smooth paste by three roller mills. The premeasured amounts of the liquids are added first to the hopper and the machine is started. The powders are added slowly and are sucked into the machine at the center of the rotor and forced across three rims into the roller mills resulting in a product showing uniformity and fineness of structure. This smooth paste was filled into collapsible tubes by fillers using the positive displacement principle prior to capping and closing of the tube.

Three patients were treated with their consent with the toothpaste formulation of Example I by the inventor, Carl M. Kosti D.D.S.

Each of the patients exhibited hypertrophy as a result of diphenylhydantoin sodium (dilantin sodium) therapy over a long period of time. Patient No. 1 was a 36 year old male receiving anticonvulsant therapy for the past six years. Patient No. 2 was a 35 year old female with a history of periodic seizures who has been under diphenylhydantoin thereapy for over eight years. Patent No. 3 was a 21 year old male epileptic who has undegone treatment for several years. The clinical manifestations of all three patients showed conditions ranging from severe hypertrophy in patient No. 1 to moderate hypertrophy in patient No. 3. The gums of each patient were red, puffy, painful and bleeding when brushed, and fibrous in some areas. Measurement of the hypertrophy was by gross oral observation and by calibrated explorer to measure the depth from the free gingival margin to the epitheliam attachment.

The treatment was effected by having the patients express approximately one inch of the toothpaste on a soft or medium hard bristle toothbrush and were instructed to gently massage the gums as the teeth were brushed for about two minutes. The patients were told not to rinse their months with water immediately after massage and brushing since such may reduce maximum absorption of the drug by the mucous membranes and retard rapid decongestion. The excess toothpaste was to be expectorated without rinsing. The treatment was carried out by the patients from two to four times a day for successive days. The gums were visually examined and measured with calibrated explorer following the first day and every day thereafter. After five days of use a substantial reduction in swelling and redness was observed, and the patients each reported that the oral cavity was vastly improved in comfort. Before treatment the patients had experienced difiiculty brushing the teeth due to profuse bleeding and pain in the gums. After treatment, no bleeding resulted on brushing and the patients were able to brush their teeth without pain. All three patients reported no apparent side effects from the use of the formulation of my invention and there was no clinical evidence of local tissue irritation or rebound congestion.

in Example I, in addition to phenylephrine hydrochloride, the vascoconstricting sympathomimetic amine, glycerin is used as a sweetening agent or vehicle in place of syrups (syrups are contraindicated in toothpastes due to their high carbohydrate content increasing the incidence of tooth decay) and to maintain the consistency of the toothpaste; proplene glycol is used in my formulation as a diluent and binder and may serve as a substitute for glycerin and alcohol; methylparaben is used as a preservative due to its inhibitory action on the microorganisms; saccharine sodium solution is used as a sweetening agent; peppermint oil is one of the many essential oils that can be used as flavoring agents; mineral oil in my invention is used as diluent; sodium lauryl sulfate is used as an emulsifier and foaming agent; dicalcium phosphate, due to its fineness is employed as an abrasive; sodium earboxymethylcellulose is used as an emulsifier and thickening and suspending agent; and distilled water in the context of my invention is used as a vehicle and dilutant.

EXAMPLE II A toothpaste was prepared as in Example I with the addition of the following ingredient:

Stannous fluoride-1 p.p.m. (one part per million) Stannous fluoride and other flouride derivatives such as sodium fluoride, monofluorophosphate, potassium flouride, etc. are effective anticariogenic substances used in toothpaste to control tooth decay by their action on the protein portion of the enamel and dentin making the said protein portions harder and subsequently more resistant to acid desolution and bacterial invasion. Such substances are generally used in concentrations of 0.25 to 10 p.p.m.

Other preservatives and their concentrations that can be used in lieu of methylparaben in the context of my invention are:

Weight percent Sodium bisulfite 0.05-0.25 Sodium benzoate 0.05-0.25 Sodium thiosulfate 0.01-0.20 Chlorobutanol 0.01-1.0 Thimerosal 0.001-0.01 Phenylmercuric acetate 0.001-0.01

The essential components of the toothpaste composition of this invention are the alkaloid in a concentration of from about 0.0125 to 5.0 weight percent, an alkaloid preservative in an amount from about 0.001 to 0.5 weight percent, a suspending agent in an amount of about 0.002 to 2.0 weight percent and from about 1 to 21 weight percent of a moisture retainer, with the balance of the composition being water.

Suitable compounds for use as the alkaloid preservative are methylparaben, propylparaben, sodium.- bisulfate, sodium benzoate, sodium thiosulfate, chlorobutanol, thimersol and henylmercuric acetate. Preferred suspending agent materials are sodium carboxymethylcellulose, methylcellulose, bentonite, acacia, sterculia gum and tragacanth. Preferred moisture retainer materials are glycerin, propylene glycol, sorbital, polyethylene glycol, diethylene glycol monoethyl ether, polysorbate, monolaurate and polyoxyethylene sorbitan.

While the toothpaste composition of this invention need only employ the alkaloid, preservative, suspending agent and moisture retainer components, excellent results have been obtained from a more balanced toothpaste formulation which included, in addition to the above components, from about 0.01 to 0.5 weight percent of a sweetening agent, about 0.01 to 1.5 of a foaming agent and about 30 to 65 weight percent of an abrasive.

Examples of abrasive materials which can be used in this invention are pumice, calcium carbonate, stannic oxide, dibasic calcium phosphate, magnesium carbonate and tribasic calcium phosphate. Suitable sweeteners include sodium cyclamate, calcium cyclamate, saccharines and sodium saccharine. Suitable foaming agents include sodium lauryl sulfate, sodium tetradecyl sulfate, sodium lauryl sarcocinate, dioctyl sodium sulfosuccinate, sulfocolaurate, thonzonium bromide, methyl benzathonium chloride, dichlorobenzalkonium chloride, dichlorobenzathonium chloride, and cetyl pyridinium chloride.

1 These compounds are preferably not used in same formulatlons with other soaps and detergents. They are cathionic surface active agents and in solution inactivate anionic surface active agents, for example soaps and detergents such as sodium lauryl sulfate. These compounds are also mildly antiseptic and bacteriostatic. Hence, they can be used where a preservative is employed.

It will be understood that one or more of the previously described addition agents may be employed in the above examples in the amounts recommended, in addition to those utilized therein, for the advantages obtained thereby; also that one or more of the addition agents used in the examples may be omitted while sacrificing their advantages. Moreover, the concentrations of the sympathomimetiamines in the examples may be varied in accordance with the recommendations previously described. Furthermore, other addendas and formulations not necessarily preferred and with or without one or more of the addition agents may be prepared using in place of the sympathomimetic agent in Example I any of the sympathomimetic agents described above. Their concentrations will readily be determined from the guide lines given for each of them, or by a few trials using the concentrations employed in the examples as guides.

From the foregoing description of the invention, it will be evident that a novel and effective composition for hypertrophied and hyperplastic or enlarged oral tissue has been provided. The treatment is simple and direct. It can be carried out by the patient and is harmless to use. Although the invention has specific application for epileptic patients who are in prolonged therapy of diphenylhydantoin sodium, it will be apparent that the compositions and treatments described above will have other applications and uses which will suggest themselves to those skilled in the art.

This invention has been described in detail with particular reference to preferred embodiments thereof, but it will be understood that variations and modifications can be elfected within the spirit and scope of the invention. The disclosure therein is by way of example and included in the invention are all modifications and equivalents falling within the scope of the appended claims.

What is claimed is:

1. A toothpaste composition containing therein an alkaloid selected from the group consisting of aromatic amines having between about 6 to carbon atoms and aliphatic amines having between about 4 to 7 carbon atoms, said alkaloid being present in an amount of from 0.0125 to 5.0 percent by weight of the toothpaste composition.

2. A toothpaste composition according to claim 1 wherein said alkaloid is selected from the group consisting of ephedrine sulfate, phenylephrine hydrochloride, cyclopentamine hydrochloride, methylhexaneamine hydrochloride, propylhexedrine hydrochloride, oxymetazoline hydrochloride and mixtures thereof.

3. A toothpaste composition according to claim 1 comprising said alkaloid, from about 0.001 to 0.5 percent of an alkaloid preservative, from about 0.002 to 2.0 percent of a suspending agent, and from 1 to 21 percent of a moisture retainer, said percentages being based on the weight of the total composition.

4. A toothpaste composition according to claim 3 wherein said alkaloid preservative is selected from the group consisting of methylparaben, propylparaben, sodium bisulfite, sodium benzoate, sodium thiosulfate, chlorobutanol, thimerosal and phenylmercuric acetate.

5. A toothpaste composition according to claim 3 wherein said suspending agent is selected from the group consisting of sodium carboxymethylcellulose, methylcellulose, bentonite, acacia, sterculia gum, and tragacanth.

6. A toothpaste composition according to claim 3 wherein said moisture retainer is selected from the group con sisting of glycerin, propylene glycol, sorbitol, polyethylene glycol, diethylene glycol monoethyl ether, polysorbate, monolaurate and polyoxyethylene sorbitan.

7. A toothpaste composition according to claim 1 consisting essentially of said alkaloid, from about 0.001 to 0.5 weight percent of an alkaloid preservative selected from the group consisting of methylparaben, propylparaben, sodium bisulfite, sodium benzoate, sodium thiosulfate, chlorobutanol, thimerosal and phenylmercurie acetate, from about 0.002 to 2.0 weight percent of a suspending agent selected from the group consisting of sodium carboxymethylcellulose, methylcellulose, bentonite, acacia, sterculia gum, and tragacanth, and from about 1 to 21 weight percent of a moisture retainer selected from the group consisting of glycerin, propylene glycol, sorbitol, polyethylene glycol, diethylene glycol monoethyl ether, polysorbate, monolaurate and polyoxyethylene sorbitan.

8. A toothpaste composition according to claim 7 further including from about 0.01 to 0.5 weight percent of a sweetening agent selected from the group consisting of sodium cyclamate, calcium cyclamate, saccharine and sodium saccharine, from about 0.01 to 1.5 weight percent of a foaming agent selected from the group consisting of sodium lauryl sulfate, sodium tetradecyl sulfate, sodium lauryl sarcocinate, dioctyl sodium sulfosuccinate, sulfocolaurate, thonzonium bromide, methyl benzathonium chloride, dichlorobenzalkonium chloride, dichlorobenzathonium chloride, and cetyl pyridinium chloride and from about 30 to weight percent of an abrasive selected from the group consisting of pumice, calcium carbonate, stannic oxide, dibasic calcium phosphate, magnesium carbonate and tribasic calcium phosphate.

References Cited UNITED STATES PATENTS RICHARD L. HUFF, Primary Examiner 

1. A TOOTHPASTE COMPOSITION CONTAINING THEREIN AN ALKALLOID SELECTED FROM THE GROUP CONSISTING OF AROMATIC AMINES HAVING BETWEEN ABOUT 6 TO 10 CARBON ATOMS AND ALIPHATIC AMINES HAVING BETWEEN ABOUT 4 TO 7 CARBON ATOMS, SAID ALKALOID BEING PRESENT IN AN AMOUNT OF FROM 0.0125 TO 5.0 PERCENT BY WEIGHT OF THE TOOTHPASTE COMPOSITION. 